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Yuan P.,Center for Genome Research | Yuan P.,Sun Yat sen Memorial Hospital | Zeng Y.,First Affiliated Hospital | Zeng Y.,Sun Yat Sen University | And 9 more authors.
Chinese Journal of Medical Genetics | Year: 2015

Objective: To explore the application of preimplantation genetic diagnosis (PGD) for infantile malignant osteopetrosis (1MO). Methods: For a family affected with IMO, PGD was provided using combined parental mutation detection and haplotype constructions with microsatellite markers spanning the TC1RG1 gene. Prenatal diagnosis was performed on the chorionic villus and amniocentesis samples by direct sequencing. Results: Prenatal diagnosis showed that the fetus by the third pregnancy has carried the parental mutations [c. 242delC (p. Pro81Argfs ∗ 85) and c. 111C>T (p. Gln372 ∗)], and the pregnancy was terminated. PGD was subsequently performed through mutations detection and haplotype analyses following whole genome amplification (WGA) of each of 13 cells. The results showed that 6 of the 13 embryos were unaffected, 3 were carriers and 4 were affected. Well developed unaffected/carrier embryos were selected and transferred into the uterus. A single pregnancy was confirmed. Subsequently pre- and post-natal diagnoses have confirmed development of a healthy child. Conclusion: The study demonstrated the advantage of PGD over prenatal diagnosis when natural pregnancies have repeatedly produced IMO children/fetuses.

Lee H.W.,Cancer Stem Cell Research Center | Lee H.W.,Samsung | Park Y.M.,Samsung | Lee S.J.,Cancer Stem Cell Research Center | And 15 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Metastatic relapse of primary lung cancer leads to therapeutic resistance and unfavorable clinical prognosis; therefore, identification of key molecules associated with metastatic conversion has significant clinical implications. We previously identified a link between early brain metastasis of lung adenocarcinoma and amplification of the a-smooth muscle actin (ACTA2) gene. The aim of present study was to investigate the prognostic and functional significance of ACTA2 expression in cancer cells for the metastatic potential of lung adenocarcinomas. Experimental Design: ACTA2 expression was analyzed in tumor cells from 263 patients with primary lung adenocarcinomas by immunohistochemistry, and was correlated with clinicopathologic parameters. The expression of ACTA2 in human lung adenocarcinoma cells was modulated with short hairpin RNAs (shRNA) and siRNAs specifically targeting ACTA2. Results: The patients with lung adenocarcinomas with high ACTA2 expression in tumor cells showed significantly enhanced distant metastasis and unfavorable prognosis. ACTA2 downregulation remarkably impaired in vitro migration, invasion, clonogenicity, and transendothelial penetration of lung adenocarcinoma cells without affecting proliferation. Consistent with the in vitro results, depletion of ACTA2 in human lung adenocarcinoma PC14PE6 cells significantly reduced their metastatic potential without altering their tumorigenic potential. Expression of c-MET and FAK in lung adenocarcinoma cells was also reduced by ACTA2-targeting siRNAs and shRNAs, and was accompanied by a loss of mesenchymal characteristics. Conclusions: These findings indicate that ACTA2 regulates c-MET and FAK expression in lung adenocarcinoma cells, which positively and selectively influence metastatic potential. Therefore, ACTA2 could be a promising prognostic biomarker and/or therapeutic target for metastatic lung adenocarcinoma. © 2013 American Association for Cancer Research.

Lee S.-T.,Sungkyunkwan University | Lee S.-T.,Center for Genome Research | Lee D.H.,Samsung | Kim J.-Y.,Soonchunhyang University | And 6 more authors.
Clinical Endocrinology | Year: 2011

Objective To investigate thyroid-stimulating hormone receptor (TSHR) and thyroid peroxidase (TPO) mutations in Korean patients with primary congenital hypothyroidism (CH). Context Congenital hypothyroidism is a common genetic disorder in which the majority of mutations occur in the TSHR and TPO genes. Design We examined the frequencies of TSHR and TPO mutations among Korean patients with primary CH. Furthermore, we explored the relationships between imaging findings and mutation status. Patients A total of 193 paediatric patients with nonsyndromic CH were enrolled in the present study. Measurements Patients with decreased 99mTc uptake were screened for TSHR mutations using Sanger sequencing, and those with increased uptake were screened for TPO mutations. The relationships between scintigraphic and ultrasonographic findings and mutation status were analysed. Results Thirteen (16·5%) of 79 patients with decreased 99mTc uptake were found to harbour TSHR mutations including G132R, G245S, R450H, R519C and F525S. The R450H mutation was present in 13 (72·2%) of 18 disease alleles. Seven (10·3%) of 68 patients with increased 99mTc uptake harboured TPO mutations including R189Q, K439E, G493S, C808LfsX72, A863T, R875Hfs and P883S. The TSHR and TPO mutations were observed only in patients with normal to slightly enlarged thyroid glands. Conclusions This study identified underlying TSHR and TPO mutations in Korean patients with CH and revealed a possible relationship between imaging findings and mutation status. In addition, the low rate of mutation positivity suggests significant genetic heterogeneity of CH in the Korean population. © 2011 Blackwell Publishing Ltd.

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